Rapid progress in understanding the epidemiology and molecular virology of human caliciviruses (HuCVs) in the past decade has highlighted the importance of HuCVs as a cause of acute gastroenteritis. The recent finding that Noroviruses (NVs) recognize human histo-blood group antigens (HBGAs) as receptors has provided new approaches to develop strategies to control and prevent NV gastroenteritis. The increasing epidemics and emergence of new epidemic variants of the globally dominant GII-4 viruses in many countries indicate that studies to increase our understanding of the role of genetic and host factors in the epidemiology and evolution of NVs are necessary. This renewal builds on the scientific productivity of the past and will seek new information to build new platforms for future development and evaluation of intervention/prevention strategies against HuCVs. 1) We will perform cryo-EM and site-directed mutagenesis analyses with NV P particles as a model to characterize the receptor binding interface and the carbohydrate interaction sites in association with the antibody-based blocking ("neutralization") of NV binding to HBGA receptors. 2) We will perform genetic and phenotypic analyses using our large collection of clinical samples to seek evidence of host factors in the evolution of NVs and to address a currently urgent important question on the epidemics or pandemics of the globally dominant GII-4 type of NVs in many countries. And finally, 3) we will take advantage of the novel rhesus enteric CV, the Tulane virus, as a model to further elucidate the virus/host interaction related to the host HBGA receptors to NVs and to use the newly developed reverse genetics system of TV to address questions related to host/pathogen interaction in attempt to developing research tools and vaccines against NVs.